Tissue-Dependent Alterations of the Clock Gene Expression Rhythms in Leptin-Resistant Zucker Diabetic Fatty Rats

Recent studies have demonstrated that circadian clocks are impaired in liver and adipose tissue of both leptin-deficient ob/ob and leptin-resistant KK-A(y) mice. Because impairment of peripheral clocks precedes metabolic abnormalities in ob/ob mice, leptin signaling might be important for modulating peripheral clocks. To assess this hypothesis, the authors determined daily mRNA expression profiles of clock genes Clock, Arntl, Per1, Per2, Cry1, Dbp, and Nr1d1 in several tissues of leptin-receptor-deficient Zucker diabetic fatty (ZDF) rats. Transcript levels of some of these genes around the respective peak times decreased significantly in the liver, but not in the suprachiasmatic nucleus, mesenteric adipose tissue, and heart, compared to those in control rats. In contrast, mRNA levels of Per1 and Dbp around the peak time increased in the aorta of ZDF rats. However, expression rhythms of these clock genes in serum-stimulated cultured cells isolated from the aorta of ZDF rats were quite similar to those in serum-stimulated aortic cells of control rats. These results show that systemic leptin signaling defect influences peripheral clocks in a tissue-dependent manner, suggesting the possibility that leptin indirectly modulates the clocks in at least a subset of peripheral tissues.